DeFrano had the bad fortune to begin his professional career just as Swing Music and Big Bands – so many of which were led by clarinet players like Artie Shaw, Benny Goodman and Woody Herman – were fading in popularity.

DeFranco was perhaps the only major jazz clarinet player to adapt to this change, and until the 1980's, he was the only notable jazz musician who played clarinet exclusively. He was also perhaps the only viable bebop clarinetist.

He performed with Gene Krupa, Charlie Barnet, Art Tatum and Count Basie and has released dozens of albums as a band leader.